Gusella, et al. have localized the HD gene to chromosome 4 (CH4) in several large multi-generational pedigrees using two linked restriction fragment polymorphisms (RFLPs). We propose to define other RFLPs linked to the HD gene as well as to investigate the possibility of genetic heterogeneity in HD by the sampling of local HD families which we have ascertained. We are constructing a sorted CH4 library for the efficient generation of RFLPs on this chromosome. The generation of CH4 RFLPs will also allow us to pursue two additional lines of research: localization of the gene(s) for peripheral neurofibromatosis (NF) and the further localization of the dentinogenesis imperfecta gene (DGI1). In different family studies NF has been shown to be linked to myotonic dystrophy (DM) on chromosome 19 (CH19) and provisionally to the group specific component (GC) on CH4. DGI1 is linked to GC. We have ascertained and will sample local NF families for the study. The DGI1 families will be obtained through Dr. P. Michael Conneally. The NF families will also be screened with our CH19 RFLPs generated as part of the large study on DM. This will allow us to confirm linkage of NF to either CH19 and/or CH4 as well as to investigate the question of genetic heterogeneity in this disease. Once a linked RFLP is found we will continue to screen our libraries in order to generate additional linkage markers. Closely linked RFLPs will be useful in both carrier detection and prenatal diagnosis. Linkage markers on either side of the disorder can also improve the accuracy of genotypic determinations. Finally, we propose to construct a general linkage map of CH4 and CH19 using our RFLPs in conjunction with CH4 and CH19 genotypic markers. We will use our DGI1, NF, and HD families as well as other large multigenerational source pedigrees (i.e. the Venezuelan pedigree, a family with familial hypercholesterolemia (FCH), and our own DM pedigrees) for the general mapping studies. Multilocus linkage analysis will also be imployed. Thus, these experiments will be instrumental in both helping to further establish the chomosomal location of the HD, NF, and DGI1 genes as well as in providing an available linkage map of CH4 and CH19, enabling investigators to link other genetic disorders to this chromosome.